857 RANDOMIZED PHASE III TRIAL OF SORAFENIB IN ADVANCED RENAL CELL CARCINOMA (RCC): IMPACT OF CROSSOVER ON SURVIVAL

857

Randomized Phase III trial of Sorafenib in Advanced Renal Cell Carcinoma (RCC): Impact of Crossover on Survival

Eisen T.1, Bukowski R.2, Staehler M.3, Szczylik C.4, Oudard S.5, Stadler W.6, Simantov R.7, Shan M.7, Escudier B.8, TARGETs Clinical Trial Group Cambridge Research Institute, Cancer Research UK, Cambridge, United Kingdom, Cleveland Clinic Cancer Center, Department of Solid Tumor Oncology, Cleveland,OH, United States of America, 3Klinikum Grosshadern, Ludwig Maximilians University, Department of Urology, Munich, Germany, 4Central Clinical Hospital of Military Medical Academy, Department of Oncology, Warsaw, Poland, 5Hopital Europeen Georges Pompidou, Department of Oncology, Paris, France, 6University of Chicago Medical Center, Department of Medicine, Section of Hematology/ Oncology, Chicago, IL, United States of America, 7Bayer Pharmaceuticals, Global Product Development, West Haven, CT, United States of America, 8Institut Gustave Roussy, Department of Immunotherapy, Villejuif, France 1

2

Introduction & Objectives: Sorafenib (Nexavar®) was approved for advanced RCC in the USA December 2005. A Phase III randomized double-blind, placebo-controlled trial demonstrated an estimated 39% improvement in survival for patients receiving sorafenib versus placebo (HR= 0.72, p= 0.018) (ECCO 2005). These data supported independently reviewed doubling of PFS to 24 weeks in RCC patients receiving sorafenib compared with placebo (12 weeks) (p<0.000001) (ASCO 2005). Based on the statistical significance and magnitude of PFS benefit, patients were unblinded and placebo patients allowed to crossover to sorafenib in April 2005. A prospectively planned interim OS analysis reflecting impact of crossover of placebo patients is presented. Material & Methods: OS data up to November 30, 2005, were analyzed in this interim analysis using a stratified log-rank test comparing the two treatment groups. In order to examine the effect of crossover on OS, a secondary analysis was performed censoring data from patients randomized to placebo at June 30, 2005. Results: A total of 903 patients were randomized (451 to sorafenib, 452 to placebo) and >200 placebo patients crossed over to sorafenib. Baseline characteristics were similar between treatment arms. There were 367 deaths. The median OS was 19.3 months for sorafenib versus 15.9 months for placebo (HR= 0.77; 95% CI 0.63, 0.95; p=0.015); although this did not attain the level of significance specified for the interim analysis (a=0.009), a continued favorable trend in survival benefit was observed. With censoring of crossover data, the median OS was 19.3 months for sorafenib versus 14.3 months for placebo (HR= 0.74, 95% CI 0.58, 0.93; p=0.010). Conclusions: Sorafenib is the first novel, oral approved treatment for advanced RCC in more than a decade. Previous information on the effect of crossover on OS in randomized oncology studies is limited. The lower HR observed after censoring placebo patients crossed over to sorafenib suggests a continued beneficial effect of sorafenib. The final overall survival analysis will be conducted once the protocol-specified 540 events have occurred. Final results await more mature data.



859



858

Safety Analysis of the Advanced Renal Cell Carcinoma Sorafenib (ARCCS) Study, an Expanded Access Program Bukowski R.1, Figlin R.2, Stadler W.3, Advanced Renal Cell Carcinoma Sorafenib (ARCCS)

Cleveland Clinic/Taussig Cancer Center, Experimental Therapeutics Program, Cleveland, United States of America, 2City of Hope National Medical Center, City of Hope Comprehensive Cancer Center, Duarte, United States of America, 3University of Chicago, Medicine/Sect Hematology-Oncology, Chicago, United States of America 1

Introduction & Objectives: Sorafenib is a multikinase inhibitor that targets tumor cell proliferation and angiogenesis. In advanced renal cell carcinoma (RCC) patients (pts), sorafenib doubled progression-free survival (PFS) and increased overall survival (OS) compared with placebo in a phase III trial (Escudier et al, ASCO 2005; ECCO 2005). Here we report preliminary safety data from the ARCCS study, an open-label, noncomparative treatment protocol for sorafenib use in advanced RCC pts. Material & Methods: Eligible pts were ≥ 15 years old with advanced (unresectable, recurrent, or metastatic) RCC, had Eastern Cooperative Oncology Group (ECOG) performance status 0–2, and were not receiving other concomitant systemic anticancer therapy (except for bisphosphanates) while taking sorafenib. Exclusion criteria included eligibility for or participation in other sorafenib trials, and investigational or standard systemic treatment within 4 weeks of study enrollment. Pts received 400 mg of sorafenib twice daily and were stratified by prior systemic antineoplastic therapy (≥ 2nd line) versus 1st line treatment. Results: Pts receiving at least 1 dose of sorafenib were evaluated for safety (n=2,337); 1,131 pts and 1,206 pts received sorafenib as 1st-line or ≥ 2nd line, respectively. Clear-cell histology accounted for 78% of cases in both groups with papillary (7%), chromophobe (1.1%), collecting duct (0.4%), oncocytoma (0.1%), and other/missing (13.4%) comprising the remainder. At study entry, 38% of pts had 1 disease site, 31% had 2, and 31% had >2. Median time from diagnosis was 1.4 years (range <1–34). Prior nephrectomy, radiotherapy, and cytokine therapy were experienced by 83%, 35%, and 39% of pts, respectively. Prior systemic therapies (n=1206) included interferon alfa (54%), interleukin 2 (43%), bevacizumab (24%), sunitinib (2%), and thalidomide (12%). Incidence of drug-related AEs (of any grade) was 71%, with 31% reporting an AE of grade 3/4. The most common AEs were hand-foot skin reaction, rash, diarrhea, fatigue, alopecia, hypertension, and nausea. For all patients (n=2337), treatmentemergent grade 3 AEs were reported in 34% of pts; 6% were grade 4. These AE occurrences were similar between 1st and ≥ 2nd line pts and rates were comparable to those reported in the phase III trial. Conclusions: The ARRCS expanded access program enrolled RCC patients representative of real world practice. The frequency of AEs was comparable among pts receiving sorafenib as 1st-line or ≥ 2nd line therapy for RCC and similar to that of the sorafenib arm in the pivotal phase III study.



860

Uncontrolled Confirmatory Trial of Single-Agent Sorafenib in Japanese Patients with Advanced Renal Cell Carcinoma

Phase III randomized trial of sunitinib malate versus interferon-alfa as first-line systemic therapy for patients with metastatic renal cell carcinoma

Akaza H.1, Naito S.2, Tsukamoto T.3, Nakajima K.4, Murai M.5

Rixe O.1, Hutson T.E.2, Tomczak P.3, Michaelson M.D.4, Bukowski R.M.5, Oudard S.6, Negrier S.7, Kim S.T.8, Chen I.8, Figlin R.A.9, Motzer R.J.10

University of Tsukuba, Department of Urology and Andrology, Tsukuba, Japan, Kyushu University, Department of Urology, Fukuoka, Japan, 3Sapporo Medical University School of Medicine, Department of Urology, Sapporo, Japan, 4Bayer Yakuhin Ltd, Product Development Division, Osaka, Japan, 5Keio University School of Medicine, Department of Urology, Tokyo, Japan 1

2

Introduction & Objectives: Sorafenib, an oral multi-kinase inhibitor, targets the Raf/MEK/ERK pathway at the level of Raf kinase and VEGF-receptor tyrosine kinases, and has shown efficacy against several tumour types in Phase II/III trials. A Phase III randomized double-blind, placebo-controlled trial in patients with advanced RCC in EU/NA demonstrated doubling of PFS to 24 weeks in patients receiving sorafenib compared with placebo (12 weeks) (p<0.000001) (ASCO 2005) and prolongation of overall survival (ASCO 2006). Now, sorafenib is approved for treatment of patients with advanced RCC in a number of countries. This study evaluated the efficacy and safety of sorafenib in Japanese RCC patients. Material & Methods: This multi-centre, uncontrolled, Phase II trial evaluated efficacy (tumour shrinkage using RECIST every 6 weeks) and safety of sorafenib (400 mg bid, continuous) in Japanese patients with advanced RCC. Eligible patients had unresectable and/or metastatic disease with measurable lesion(s) and prior cytokine-therapy with IFN-α or IL-2 (1-3 therapies). Results: One hundred thirty one patients received sorafenib. Nineteen patients (14.7%) had confirmed partial response (PR) and 93 patients (72.1%) had stable disease (SD) out of 129 patients evaluable for efficacy by investigator assessment. One hundred three patients (79.8%) had some degree of tumour shrinkage (Figure below). Median progression-free survival (PFS) was 32 weeks in all patients, and PFS rate at 6 months after treatment was 0.59 and 0.88 in SD and PR cases, respectively. In this patient population who failed prior cytokine therapy, the clinical benefit resulting from sorafenib treatment may be associated with an improvement in survival. The most frequent drug-related adverse events observed in 131 patients evaluable for safety were skin toxicities, asymptomatic pancreatic enzyme elevation and hypertension: hand–foot skin reaction (HFS; 72 [55.0%]), rash/desquamation (49 [37.4%]), lipase elevation (73 [55.7%]), amylase elevation (50 [38.2%]), and hypertension (36 [27.5%]). Among them, grade 3/4 included lipase elevation (40 [30.5%]), hypertension (16 [12.2%]), and HFS (12 [9.2%]). Nineteen patients discontinued due to adverse events. Conclusions: Sorafenib 400 mg bid showed promising efficacy and was generally well tolerated in Japanese patients with advanced RCC similar to patients in the EU/NA. Improvement in PFS was evident among patients achieving clinical benefit (PR + SD) with sorafenib treatment; the use of clinical benefit rate may be an appropriate measure of the efficacy of sorafenib.

l’Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France, 2Baylor Sammons Cancer Center, Texas Oncology, Dallas, United States of America, 3Klinika Onkologii Oddzial Chemioterapii, Klinika Onkologii, Poznan, Poland, 4Massachusetts General Hospital, Cancer Center, Boston, United States of America, 5Cleveland Clinic Foundation, Taussig Cancer Center, Cleveland, United States of America, 6Hôpital Européen Georges-Pompidou, Department of Oncology, Paris, France, 7Centre Léon Bérard, Department of Oncology, Lyon, France, 8Pfizer, Global Research and Development, La Jolla, United States of America, 9City of Hope Comprehensive Cancer Center, Department of Medicine, LA, United States of America, 10Memorial Sloan-Kettering Cancer Center, Genitourinary Oncology Service, New York, United States of America 1

Introduction & Objectives: Sunitinib malate (SUTENT®) is an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities due to inhibition of multiple receptors, including VEGFR, PDGFR, KIT, RET and FLT3. In two, multicenter phase II trials of second-line monotherapy in patients with metastatic renal cell carcinoma (mRCC), 42% of patients achieved an objective tumor response (pooled analysis, n=168; JAMA 2006;295:2516–24). Exceeding the response rates reported for cytokines as first-line treatment (5–20%), these data provided the rationale for investigating sunitinib in the first-line setting compared to conventional cytokine therapy. We report here the results of an international, randomized phase III trial that compared the efficacy and safety of sunitinib to interferonalfa (IFN-α) as first-line therapy in patients with mRCC. Material & Methods: 750 mRCC patients with no prior systemic therapy were randomized 1:1 to receive sunitinib in 6-week cycles (50 mg orally once daily for 4 weeks, followed by 2 weeks off) or IFN-α (9 MU subcutaneous injection three times weekly). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival, and safety. The trial was designed to detect a clinically relevant improvement in PFS from 4.6 to 6.2 months, i.e. 35% improvement, using a 2-sided unstratified log-rank test with an overall 2-sided significance level of 0.05 and 90% power. Results of a planned analysis are presented in this report. Results: Between August 2004 and October 2005, 750 patients were randomized to treatment, 375 to sunitinib and 375 to IFN-α. The treatment groups were well balanced with respect to baseline demographic and disease characteristics; the pooled median age was 60 years and 90% of patients had prior nephrectomy. The median PFS by independent central review was 11 months for sunitinib vs. 5 months for IFN-α [hazard ratio, 0.415 (95% CI: 0.320–0.539); P<0.000001]. The ORR by independent central review was 31% for sunitinib vs. 6% for IFN-α (P<0.000001). The ORR by investigator assessment was 37% for sunitinib vs. 9% for IFN-α (P<0.000001). At the time of analysis, 248 patients (66%) were continuing treatment with sunitinib vs. 126 patients (34%) with IFN-α. Eight percent of patients in the sunitinib group withdrew from the study due to an adverse event vs. 13% in the IFN-α group. Conclusions: This study demonstrated a statistically significant improvement in PFS and ORR for sunitinib compared with IFN-α in the first-line treatment of patients with mRCC.

Eur Urol Suppl 2007;6(2):237